Inhibition of airway proteases in cystic fibrosis lung disease

Griese, Matthias; Kappler, Matthias; Gaggar, Amit; Hartl, Dominik

doi:10.1183/09031936.00146807

Cited by 94 publications

(87 citation statements)

References 138 publications

(137 reference statements)

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“…This sustained inflammatory response recruits neutrophils in an attempt to resolve bacterial infection, yet paradoxically, chronic neutrophil stimulation also leads to neutrophil necrosis (9). As a consequence, neutrophils are not cleared effectively and neutrophil contents, including proteases, are released into the lung perpetuating the inflammatory cycle (10). Thus, a better understanding of the mechanisms involved in inducing and controlling inflammation is required for the successful design of novel intervention strategies in CF.…”

mentioning

confidence: 99%

Dysregulation of TIM-3–Galectin-9 Pathway in the Cystic Fibrosis Airways

Vega-Carrascal

Reeves

Niki

et al. 2011

The Journal of Immunology

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The T-cell Ig and mucin domain-containing molecules (TIMs) have emerged as promising therapeutic targets to correct abnormal immune function in several autoimmune and chronic inflammatory conditions. It has been reported that proinflammatory cytokine dysregulation and neutrophil-dominated inflammation are the main causes of morbidity in cystic fibrosis (CF). However, the role of TIM receptors in CF has not been investigated. In this study, we demonstrated that TIM-3 is constitutively overexpressed in the human CF airway, suggesting a link between CF transmembrane conductance regulator (CFTR) function and TIM-3 expression. Blockade of CFTR function with the CFTR inhibitor-172 induced an upregulation of TIM-3 and its ligand galectin-9 in normal bronchial epithelial cells. We also established that TIM-3 serves as a functional receptor in bronchial epithelial cells, and physiologically relevant concentrations of galectin-9 induced TIM-3 phosphorylation, resulting in increased IL-8 production. In addition, we have demonstrated that both TIM-3 and galectin-9 undergo rapid proteolytic degradation in the CF lung, primarily because of neutrophil elastase and proteinase-3 activity. Our results suggest a novel intrinsic defect that may contribute to the neutrophil-dominated immune response in the CF airways.

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mentioning

confidence: 99%

Dysregulation of TIM-3–Galectin-9 Pathway in the Cystic Fibrosis Airways

Vega-Carrascal

Reeves

Niki

et al. 2011

The Journal of Immunology

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“…Secreted actively (as a consequence of cell activation) or passively (as a consequence of necrotic cell death), neutrophil serine proteases (NSPs; e.g., neutrophil elastase [NE], cathepsin G [CG], and proteinase 3 [PR3]) are major contributors to neutrophil dysfunction. NE is considered a major contributor to a range of pulmonary pathologies, including cystic fibrosis (CF) (1)(2)(3), and is an important therapeutic target (3). Under well-controlled conditions in otherwise healthy individuals, NSPs contribute to the effective control of infection.…”

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confidence: 99%

“…Under well-controlled conditions in otherwise healthy individuals, NSPs contribute to the effective control of infection. However, excessive and poorly regulated NSP activity contributes to disease in a number of ways (3). In addition to their direct elastolytic activity toward lung tissue, NSPs also have the capacity to substantially modulate local inflammatory responses through proteolysis of cytokines and chemokines and their receptors [e.g., IL-6, CXCR1, and soluble IL-6R (4,5)] and innate immune recognition molecules including the complement receptor (CR) for C3b (CR1), its ligand C3bi (6,7), and C-type lectins including surfactant proteins A and D (8,9).…”

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confidence: 99%

Mechanism of Neutrophil Dysfunction: Neutrophil Serine Proteases Cleave and Inactivate the C5a Receptor

Berg

Tambourgi

Clark

et al. 2014

The Journal of Immunology

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Neutrophil dysfunction, resulting in inefficient bacterial clearance, is a feature of several serious medical conditions, including cystic fibrosis (CF) and sepsis. Poorly controlled neutrophil serine protease (NSP) activity and complement activation have been implicated in this phenomenon. The capacity for excess NSP secretion and complement activation to influence the expression and function of the important neutrophil-activating receptor C5aR was investigated. Purified NSPs cathepsin G (CG), neutrophil elastase (NE), and proteinase 3 cleaved C5aR to a 26- to 27-kDa membrane-bound fragment, thereby inactivating its C5a-induced signaling ability. In a supernatant transfer assay, NSPs released from neutrophils in response to C5a induced the cleavage of the C5aR on unstimulated cells. Stimulation of myeolomonocytic U937 cells and purified neutrophils with C5a resulted in downregulation of the C5aR on these cells, which, in the case of U937 cells, was largely caused by NSP-mediated cleavage of C5aR, but in the case of neutrophils, intracellular degradation was likely the main mediator in addition to a small role for NSPs. CG and NE in bronchoalveolar lavage fluid from CF patients both contributed to C5aR cleavage. We propose two converging models for C5a- and NSP-mediated neutrophil dysfunction whereby C5aR cleavage is induced by NSPs, secreted in response to: 1) excess C5a generation or other stimuli; or 2) necrosis. The consequent impairment of C5aR activity contributes to suboptimal local neutrophil priming and bacterial clearance. NSP inhibitors with specificity for both CG and NE may aid the treatment of pathologies associated with neutrophil dysfunction including sepsis and CF.

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“…As delayed mucociliary clearance continues, persistent bacterial colonization leads to an aggressive and exaggerated inflammatory response with the ongoing influx of PMNs into the airways. PMNs release a variety of inflammatory products (such as myeloperoxidase, lactoferrin, and various proteases) causing airway epithelial damage and extracellular matrix remodeling [10-12]. This release can be carefully coordinated or may be as a result of PMN apoptosis or necrosis [13].…”

Section: Introductionmentioning

confidence: 99%

Proline-Glycine-Proline (PGP) and High Mobility Group Box Protein-1 (HMGB1): Potential Mediators of Cystic Fibrosis Airway Inflammation

Gaggar

Rowe²,

Hardision³

et al. 2010

TORMJ

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Cystic fibrosis (CF) is chronic lung disease characterized by an unrelenting neutrophil-predominant airway inflammatory response. This inflammation leads to extracellular matrix (ECM) remodeling and eventually to the development of bronchiectasis. While many components of the immune response in CF have been well-characterized, recent data suggests that small molecules may play an important and underappreciated role in this inflammation. This review will examine two novel molecules: proline-glycine-proline (PGP) and high mobility group box protein-1 (HMGB1), and their potential impact in CF lung disease. This review will provide a brief overview of CF lung disease and background on both HMGB1 and PGP. It will then focus on these molecules in a murine model of CF-like airway disease and in human biological specimens from CF individuals. Finally, this manuscript will address possible mechanisms for therapeutic targeting of these bioactive mediators.

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Inhibition of airway proteases in cystic fibrosis lung disease

Cited by 94 publications

References 138 publications

Dysregulation of TIM-3–Galectin-9 Pathway in the Cystic Fibrosis Airways

Dysregulation of TIM-3–Galectin-9 Pathway in the Cystic Fibrosis Airways

Mechanism of Neutrophil Dysfunction: Neutrophil Serine Proteases Cleave and Inactivate the C5a Receptor

Proline-Glycine-Proline (PGP) and High Mobility Group Box Protein-1 (HMGB1): Potential Mediators of Cystic Fibrosis Airway Inflammation

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